fragment based drug discovery and x-ray crystallography

317 Topics in Current Chemistry Editorial Board: K.N. Houk l C.A. Hunter l M.J. Krische l J M. Lehn S.V. Ley l M. Olivucci l J. Thiem l M. Venturi l P. Vogel C H. Wong l H. Wong l H. Yamamoto Topics in Current Chemistry Recently Published and Forthcoming Volumes Fragment-Based Drug Discovery and X-Ray Crystallography Volume Editors: Thomas G. Davies, Marko Hyvo ¨ nen Vol. 317, 2012 Novel Sampling Approaches in Higher Dimensional NMR Volume Editors: Martin Billeter, Vladislav Orekhov Vol. 316, 2012 Advanced X-Ray Crystallography Volume Editor: Kari Rissanen Vol. 315, 2012 Pyrethroids: From Chrysanthemum to Modern Industrial Insecticide Volume Editors: Noritada Matsuo, Tatsuya Mori Vol. 314, 2012 Unimolecular and Supramolecular Electronics II Volume Editor: Robert M. Metzger Vol. 313, 2012 Unimolecular and Supramolecular Electronics I Volume Editor: Robert M. 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Davies Astex Pharmaceuticals 436 Cambridge Science Park Milton Road Cambridge CB4 0QA UK tom.davies@astx.com Dr. Marko Hyvo ¨ nen Department of Biochemistry University of Cambridge 80 Tennis Court Road Cambridge CB2 1GA UK marko@cryst.bioc.cam.ac.uk ISSN 0340-1022 e-ISSN 1436-5049 ISBN 978-3-642-27539-5 e-ISBN 978-3-642-27540-1 DOI 10.1007/978-3-642-27540-1 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011945781 # Springer-Verlag Berlin Heidelberg 2012 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. 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Hunter Department of Chemistry University of Sheffield Sheffield S3 7HF, United Kingdom c.hunter@sheffield.ac.uk Prof. Michael J. Krische University of Texas at Austin Chemistry & Biochemistry Department 1 University Station A5300 Austin TX, 78712-0165, USA mkrische@mail.utexas.edu Prof. Dr. Jean-Marie Lehn ISIS 8, alle ´ e Gaspard Monge BP 70028 67083 Strasbourg Cedex, France lehn@isis.u-strasbg.fr Prof. Dr. Steven V. Ley University Chemical Laboratory Lensfield Road Cambridge CB2 1EW Great Britain Svl1000@cus.cam.ac.uk Prof. Dr. Massimo Olivucci Universita ` di Siena Dipartimento di Chimica Via A De Gasperi 2 53100 Siena, Italy olivucci@unisi.it Prof. Dr. Joachim Thiem Institut fu ¨ r Organische Chemie Universita ¨ t Hamburg Martin-Luther-King-Platz 6 20146 Hamburg, Germany thiem@chemie.uni-hamburg.de Prof. Dr. Margherita Venturi Dipartimento di Chimica Universita ` di Bologna via Selmi 2 40126 Bologna, Italy margherita.venturi@unibo.it Dr. Thomas G. Davies Astex Pharmaceuticals 436 Cambridge Science Park Milton Road Cambridge CB4 0QA UK tom.davies@astx.com Dr. Marko Hyvo ¨ nen Department of Biochemistry University of Cambridge 80 Tennis Court Road Cambridge CB2 1GA UK marko@cryst.bioc.cam.ac.uk Prof. Dr. Pierre Vogel Laboratory of Glycochemistry and Asymmetric Synthesis EPFL – Ecole polytechnique fe ´ derale de Lausanne EPFL SB ISIC LGSA BCH 5307 (Bat.BCH) 1015 Lausanne, Switzerland pierre.vogel@epfl.ch Prof. Dr. Chi-Huey Wong Professor of Chemistry, Scripps Research Institute President of Academia Sinica Academia Sinica 128 Academia Road Section 2, Nankang Taipei 115 Taiwan chwong@gate.sinica.edu.tw Prof. Dr. Henry Wong The Chinese University of Hong Kong University Science Centre Department of Chemistry Shatin, New Territories hncwong@cuhk.edu.hk Prof. Dr. Hisashi Yamamoto Arthur Holly Compton Distinguished Professor Department of Chemistry The University of Chicago 5735 South Ellis Avenue Chicago, IL 60637 773-702-5059 USA yamamoto@uchicago.edu vi Editorial Board Topics in Current Chemistry Also Available Electronically Topics in Current Chemistry is included in Springer’s eBook package Chemistry and Materials Science. 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Aims and Scope The series Topics in Current Chemistry presents critical reviews of the present and future trends in modern chemical research. The scope includes all areas of chemical science, including the interfaces with related disciplines such as biology, medicine, and materials science. The objective of each thematic volume is to give the non-specialist reader, whether at the university or in industry, a comprehensive overview of an area where new insights of interest to a larger scientific audience are emerging. vii Thus each review within the volume critically surveys one aspect of that topic and places it within the context of the volume as a whole. The most significant developments of the last 5–10 years are presented, using selected examples to illus- trate the principles discussed. A description of the laboratory procedures involved is often useful to the reader. The coverage is not exhaustive in data, but rather conceptual, concentrating on the methodological thinking that will allow the non- specialist reader to understand the information presented. Discussion of possible future research directions in the area is welcome. Review articles for the individual volumes are invited by the volume editors. In references Topics in Current Chemistry is abbreviated Top Curr Chem and is cited as a journal. Impact Factor 2010: 2.067; Section “Chemistry, Multidisciplinary”: Rank 44 of 144 viii Topics in Current Chemistry Also Available Electronically Preface The fragment-based approach has emerge d in the last decade as a highly promising component of modern drug discovery. Despite its relatively short history, it has been the subject of many research articles, reviews and books, and is responsible for several compounds currently in clinical development. Its contribution is increas- ingly recognized by the medicinal chemistry community, and it now forms an important part of drug discovery efforts within the pharmaceutical industry. Despite the exponential growth of interest in this field, fragment-based drug discovery (FBDD) represents a significant paradigm shift for drug discoverers, both philosophically, and in terms of methodology and work-flow. In particular, it has required a shift away from relatively potent, drug-like hits, readily identified by enzymatic high-throughput assays, to the more challenging detection of very weakly (but efficiently) binding compounds. As such, the development and appli- cation of robust and sensitive biophysical techniques to detect and characterise the binding of simple, low molecular compounds has been a key part of enabling this approach. X-ray crystallography was one of the earliest techniques demonstrated to be capable of detecting the binding of fragments, and its addi tional ability to provide precise three-dimensional detail on their binding modes, and hence guide their subsequent elaboration has led to it playing a central role in this approach. In this volume we bring together chapters by a number of practitioners in the field, drawn from both the pharmaceutical industry and academia. Our aim has been to highlight the important roles that X-ray crystallography plays in the fragment- approach: as a sensitive technique for primary screening, its use in combination with other biophysical techniques to allow robust hit validation, and its importance in providing structural information to guide progression from hit to clinical candi- date. In the first chapter, Erlanson from Carmot Therapeutics provides an introduction to the FBDD field as a whole, highlighting some of the advantages of fragments and their means of detection, and giving examples of fragment-derived compounds which have already reached the clinic. Davies and Tickle from Astex Therapeutics then provide a review of the use of X-ray crystallography for fragment screening, ix and describe some of the computational developments developed at Astex that have allowed the rapid generation of protein-ligand structural data required for this approach. In chapter 3, Roughley and colleagues from Vernalis present the first of a number of personal case studies of FBDD – in this case, the application of the fragment-approach to the development of Hsp90 inhibitors, with emphasis on the role of in silico screening, and its interplay with experimental structural informa- tion. This is followed by a chapter from Wyss et al (Merck), who describe their work on the fragment-based development of BACE inhibitors and how comple- mentary information from both NMR and X-ray crystallography were combined to successfully prosecute a drug discovery campaign against this important target. Continuing on the theme of combining biophysical techniques, Hennig and collea- gues then describe the approach to FBDD taken at Roche, and in particular how Surface Plasmon Resonance and structural information are used together in an integrated approach. Fragment-based approaches are increasing ly being applied to challenging thera- peutic targets, and in particular those for which conventional drug discovery methods have failed. In chapter 6, Valkov and colleagues (University of Cambridge) provide a review of small molecule inhibition of protein-protein inter- actions, and the application of fragment-based methods against this class of target. Bauman et al (Rutgers) then describe the use of X-ray crystallographic fragment screening to identify novel hits against HIV targets, and highlight the growing trend for academic-based FBDD. Indeed, the close associa tion of biophysical and struc- tural techniques, combined with the manageable size of screening libraries make fragment-based methods increasingly appealing and accessible to academic labora- tories in addition to those in the pharmaceutical industry. In the concluding chapter, and in a departure from the predominantly experi- mental methods discussed above, Rognan (University of Strasbourg) provides a computational perspective on the fragment-based approach, and discusses the application and development of in silico approaches which are increasingly being applied in this area. We hope this book will provide a useful introduction to some of the key concepts and techniques in fragment-based drug discovery, highlighting the diverse set of targets it is applied to, as well as emphasizing the importance of structura l infor- mation in this field. The application of X-ray crystallography to structure-based drug discovery is now a mature discipline, but one whose potential has sometimes been under-exploited. In driving various aspects of the fragment-based approach, it clearly plays a central role. Cambridge, January 2012 Thomas Davies Marko Hyvo ¨ nen x Preface [...]... Fragment- Based Drug Discovery 1 Daniel A Erlanson Fragment Screening Using X-Ray Crystallography 33 Thomas G Davies and Ian J Tickle Hsp90 Inhibitors and Drugs from Fragment and Virtual Screening 61 Stephen Roughley, Lisa Wright, Paul Brough, Andrew Massey, and Roderick E Hubbard Combining NMR and X-ray Crystallography in Fragment- Based Drug Discovery: ... for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement Keywords Fragment- based drug discovery Á Fragment- based lead discovery Á Fragment- based screening Á Kinase Á Nuclear magnetic resonance spectroscopy Á Structure -based drug design Á X-ray crystallography Contents 1 2 Why Fragments? ... (now Merck), and Vernalis NMR approaches have been extensively reviewed [29, 36–45], and are also covered in more depth by Wyss and coworkers [46] 2.2.2 X-Ray Crystallography X-ray crystallography is covered in detail by Bauman et al [47], Davies and Tickle [48], and Hennig et al [49] and will thus be only briefly discussed here Introduction to Fragment- Based Drug Discovery 9 Crystallography and protein-detected... Discovery: Discovery of Highly Potent and Selective BACE-1 Inhibitors Daniel F Wyss, Yu-Sen Wang, Hugh L Eaton, Corey Strickland, Johannes H Voigt, Zhaoning Zhu, and Andrew W Stamford 83 Combining Biophysical Screening and X-Ray Crystallography for Fragment- Based Drug Discovery 115 Michael Hennig, Armin Ruf, and Walter Huber Targeting Protein–Protein Interactions and Fragment- Based. .. 2011 Introduction to Fragment- Based Drug Discovery Daniel A Erlanson Abstract Fragment- based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs These fragments are then expanded or linked together to generate drug leads Although the... Fragment- based approaches in drug discovery, 2006; Zartler and Shapiro, Fragmentbased drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011) However, this chapter will assume that the reader is approaching the field with little prior knowledge It will introduce some of the key concepts, set the stage for the chapters to follow, and. .. Protein–Protein Interactions and Fragment- Based Drug Discovery 145 ¨ Eugene Valkov, Tim Sharpe, May Marsh, Sandra Greive, and Marko Hyvonen Fragment Screening and HIV Therapeutics 181 Joseph D Bauman, Disha Patel, and Eddy Arnold Fragment- Based Approaches and Computer-Aided Drug Discovery 201 Didier Rognan Index... ligands bind to proteins Unlike NMR, crystallography can be applied to large proteins and can provide very high-resolution data Fragmentbased drug discovery owes much to the rapid increase in throughput of crystallography over the past 15 years Most companies using FBDD now use X-ray crystallography Some companies use crystallography as their primary screening technique, and several only pursue fragments... Evaluating Fragments 11 3.1 What Is a Fragment? 12 3.2 Weak Versus Low Affinity: The Importance of Ligand Efficiency 12 4 What Is Fragment- Based Drug Discovery? 13 5 Success Stories in Fragment- Based Drug Discovery: ... illustrates the potential of fragment- based approaches to seek out and explore new regions of chemical space 5.4 Fragment- Assisted Drug Discovery Earlier in this chapter the notion of fragment- assisted drug discovery was discussed, in which fragment information is used to inform a medicinal chemistry program The example given here describes how structural information provided from fragment screening contributed . Lisa Wright, Paul Brough, Andrew Massey, and Roderick E. Hubbard Combining NMR and X-ray Crystallography in Fragment-Based Drug Discovery: Discovery of Highly Potent and Selective BACE-1 Inhibitors. Strickland, Johannes H. Voigt, Zhaoning Zhu, and Andrew W. Stamford Combining Biophysical Screening and X-Ray Crystallography for Fragment-Based Drug Discovery 115 Michael Hennig, Armin Ruf, and. follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement. Keywords Fragment-based drug discovery Á Fragment-based lead discovery Á Fragment-based